The BWH Udall Center utilizes a range of experimental approaches, from biophysics and animal modeling to drug discovery, to elucidate the underlying cause of Parkinson's disease. The ultimate goal of this work is to identify new therapeutic targets for PD, to test the validity of these targets, and to identify drug-like molecules that modify'these targets in animal models and ameliorate disease. Four genes have been linked to rare forms of inherited disease, and it is our hypothesis that these genes will lead us to the underlying cause of the common sporadic forms of disease as well. These genes encode the following four proteins: (1) a-synuclein, the fibrillar component of the disease-associated Lewy body, (2) UCH-L1, an enzyme involved in protein ubiquitination and/or degradation, (3) parkin, another enzyme involved in protein ubiquitination arid/or degradation, and (4) DJ-1, a protein of unknown function. The basic strategy of our center is to determine the effects of the PD mutations on each of these. Three basic approaches will be utilized: (1) biochemistry (project 1), (2) cell biology (project 2), and mouse modeling (project 3). In addition to these basic studies, the BWH Udall Center houses two core facilities that are intended to facilitate the translation of our discoveries into new therapeutics. A high-throughput drug screening core (core A) is utilized to identify drug-like molecules that reverse the effects of PD mutations in test-tube models of disease. Such molecules will be tested in animal models of disease. To enable the first step in such testing, a core facility for testing of drug-like compounds in Parkinsonian drosophila has been established (core B).